Muscarinic Inhibition of Calcium Current and M Current in Gα q -Deficient Mice

Activation of M 1 muscarinic acetylcholine receptors (M 1 mAChR) inhibits M-type potassium currents ( I K(M) ) and N-type calcium currents ( I Ca ) in mammalian sympathetic ganglia. Previous antisense experiments suggested that, in rat superior cervical ganglion (SCG) neurons, both effects were partly mediated by the G-protein Gα q (Delmas et al., 1998a; Haley et al., 1998a), but did not eliminate a contribution by other pertussis toxin (PTX)-insensitive G-proteins. We have tested this further using mice deficient in the Gα q gene. PTX-insensitive M 1 mAChR inhibition of I Ca was strongly reduced in Gα q −/− mouse SCG neurons and was fully restored by acute overexpression of Gα q . In contrast, M 1 mAChR inhibition of I K(M) persisted in Gα q −/− mouse SCG cells. However, unlike rat SCG neurons, muscarinic inhibition of I K(M) was partly PTX-sensitive. Residual (PTX-insensitive) I K(M) inhibition was slightly reduced in Gα q −/− neurons, and the remaining response was then suppressed by anti-Gα q/11 antibodies. Bradykinin (BK) also inhibits I K(M) in rat SCG neurons via a PTX-insensitive G-protein (G q and/or G 11 ; Jones et al., 1995). In mouse SCG neurons, I K(M) inhibition by BK was fully PTX-resistant. It was unchanged in Gα q −/− mice but was abolished by anti-Gα q/11 antibody. We conclude that, in mouse SCG neurons (1) M 1 mAChR inhibition of I Ca is mediated principally by G q , (2) M 1 mAChR inhibition of I K(M) is mediated partly by G q , more substantially by G 11 , and partly by a PTX-sensitive G-protein(s), and (3) BK-induced inhibition of I K(M) is mediated wholly by G 11 .